Food and drug administration




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FOOD AND DRUG ADMINISTRATION


CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


MEETING OF THE


BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE


8:15 a.m.


Thursday, July 15, 1999


Versailles Ballrooms I and II

Holiday Inn

8120 Wisconsin Avenue

Bethesda, Maryland 20814

ATTENDEES


COMMITTEE MEMBERS:


DANIEL R. SALOMON, M.D., Acting Chairman

Associate Professor

Department of Molecular and Experimental

Medicine - SBR5

The Scripps Research Institute

10550 North Torrey Pines Road

La Jolla, California 92037


GAIL DAPOLITO, Executive Secretary

Scientific Advisors and Consultants Staff

Center for Biologics Evaluation and Research

Food and Drug Administration

1401 Rockville Pike

Rockville, Maryland 20852-1448


HUGH AUCHINCLOSS, JR., M.D.

Associate Professor of Surgery

Harvard Medical School

Transplantation Unit

Department of Surgery

Massachusetts General Hospital

GRB504, 55 Fruit Street

Boston, Massachusetts 02144-2696


RICHARD E. CHAMPLIN, M.D.

Professor of Medicine

Division of Medicine

Department of Blood and Marrow Transplantation

University of Texas M.D. Anderson Cancer Center

1515 Holcombe Boulevard, Box 24

Houston, Texas 77030


RICHARD A. GOLDSBY, Ph.D.

(attending via teleconference call)

Professor of Biology

Department of Biology

Merrill Science Center, Campus Box 2237

Amherst College

Amherst, Massachusetts 01002

ATTENDEES (Continued)


COMMITTEE MEMBERS: (Continued)


CAROLE B. MILLER, M.D.

Associate Professor of Oncology

The Johns Hopkins Oncology Center

600 North Wolfe Street, Room 132

Baltimore, Maryland 21287-8985


W. MICHAEL O'FALLON, Ph.D.

Professor of Biostatistics

Chair, Department of Health Sciences Research

Harwick Building, Room 766-A

Mayo Clinic

Rochester, Minnesota 55905


EDWARD A. SAUSVILLE, M.D., Ph.D.

Associate Director

Developmental Therapeutics Program

Division of Cancer Treatment

National Cancer Institute

6130 Executive Boulevard

Executive Plaza, North Room 843

Bethesda, Maryland 20892


TEMPORARY VOTING MEMBERS:


VIRGINIA C. BROUDY, M.D.

Associate Professor of Medicine

Department of Medicine

Division of Hematology, Room K136

University of Washington School of Medicine

Seattle, Washington 98195


ABBEY S. MEYERS, Consumer Representative

President and Executive Director

National Organization for Rare Disorders

Fairwood Professional Building

Post Office Box 8923

New Fairfield, Connecticut 06812-8923


JULIE M. VOSE, M.D.

Vice Chairman and Professor

Department of Internal Medicine

University of Nebraska Medical Center

983332 Nebraska Medical Center

Omaha, Nebraska 68198-3332

ATTENDEES (Continued)


FOOD AND DRUG ADMINISTRATION STAFF:


JOSEPH B. BEKISZ

BETTY GOLDMAN, M.S., M.P.H.

PATRICIA KEEGAN, M.D.

AMY S. ROSENBERG, M.D.

WILLIAM SCHWIETERMAN, M.D.

JAY P. SIEGEL, M.D.

KATHRYN E. STEIN, M.D.

KAREN D. WEISS, M.D.

KATHRYN C. ZOON, Ph.D.


ALSO PRESENT:


THOMAS SCHAIBLE, Ph.D.

Senior Director, Immunology Medical Affairs

Centocor, Inc.

C O N T E N T S


AGENDA ITEM PAGE


ADMINISTRATIVE REMARKS - by Ms. Gail Dapolito 8


OPEN PUBLIC HEARING

Dr. Thomas Schaible, Centocor, Inc. 10


TOPIC I - FDA REGULATORY POLICY UPDATE


Fast Track/Evidence of Effectiveness -

by Dr. Jay Siegel 27


Pediatric Rule - by Dr. Karen Weiss 77


TOPIC II - REPORT OF THE XENOTRANSPLANTATION

SUBCOMMITTEE, JUNE 3-4, 1999 MEETING

by Dr. Hugh Auchincloss 114


PRESENTATION OF CERTIFICATES

by Dr. Kathryn Zoon and Dr. Jay Siegel 126


TOPIC III - IMMUNE REACTIONS AGAINST THERAPEUTIC

AND DIAGNOSTIC BIOLOGICAL PRODUCTS

FDA Perspective:


Immunogenicity of Therapeutic Proteins

by Dr. Kathryn Zoon 130


Immunogenicity of Monoclonal Antibody

Products - by Dr. Kathryn Stein 134


Immunogenicity of Interferons

by Mr. Joseph Bekisz 153


Immunogenicity of Other Therapeutic Proteins

by Dr. Amy Rosenberg 169


Clinical Perspective -

by Dr. William Schwieterman 193


Committee Discussion of Questions Presented 213

P R O C E E D I N G S

(8:15 a.m.)

DR. SALOMON: Good morning, everybody. I'm going to open the meeting today. My name is Dan Salomon, and I'm a member of the Scripps Research Institute in La Jolla, California.

I'm going to act as the acting Chair today. It just seems a little strange to me -- I've already noted that -- with having Dr. Vose to my left who, ever since I've been on the committee, has been the Chairperson and basically been for me a role model for what a Chair should be of this kind of a committee. I can only be a facsimile of Dr. Vose. I've asked her to just sort of elbow me from time to time if I'm not doing it right. But anyway, I apologize. I really won't be able to do as good a job as she does.

The meeting today will start in a moment, but I thought what we ought to do, just to begin, is go around the table and introduce everyone and everyone just sort of briefly tell us what institution they are from and what their basic clinical or scientific interests are. If we can start on the left.

DR. O'FALLON: I'm Michael O'Fallon from the Mayo Clinic. My expertise is in biostatistics.

DR. CHAMPLIN: Richard Champlin from the M.D. Anderson Cancer Center and the Chairman of the Blood and Marrow Transplant Department.

DR. SAUSVILLE: I'm Ed Sausville from the National Cancer Institute and the Developmental Therapeutics Program, and my interest is in the development of new drugs for the treatment of cancer.

DR. VOSE: Julie Vose from the University of Nebraska Medical Center, and my research interests are in lymphoma and hematologic malignancies, transplantation, and immunotherapy.

DR. SALOMON: Again, as I said, Dan Salomon, Scripps Research Institute. My interests are in transplantation, xenotransplantation, and gene therapy.

MS. DAPOLITO: Gail Dapolito, Executive Secretary for the committee.

I'd also like to announce that Dr. Richard Goldsby from Amherst College is participating on the speaker phone this morning.

I'd also like to take this opportunity to introduce Ms. Rosanna Harvey, the committee management specialist. As the committee knows, Rosanna was instrumental in the preparations for today's meetings, and as usual, she'll be around all day to help out with any questions.

Thank you.

DR. BROUDY: I'm Virginia Broudy from the University of Washington, and my interest is in hematopoietic growth factors.

MS. MEYERS: Abbey Meyers, President of the National Organization for Rare Disorders, which is NORD. I'm a former member of the committee I believe and a consultant today for consumers.

DR. MILLER: Carole Miller from Johns Hopkins. My interests are in hematologic malignancies and bone marrow transplant, clinical.

DR. STEIN: Kathryn Stein, Director of the Division of Monoclonal Antibodies, CBER.

DR. SCHWIETERMAN: Bill Schwieterman, Chief of the Immunology and Infectious Disease Branch, CBER.

DR. SIEGEL: Jay Siegel, Office of Therapeutics at CBER.

DR. SALOMON: Yes. I'd also like to add that Dr. Hugh Auchincloss from Harvard Medical School will be joining us in a few minutes.

Next Gail will read into the record the administrative remarks.

MS. DAPOLITO: This announcement is made part of the record at this meeting of the Biological Response Modifiers Advisory Committee on July 15.

Pursuant to the authority granted under the committee charter, the Director of the FDA's Center for Biologics Evaluation and Research has appointed Dr. Virginia Broudy, Ms. Abbey Meyers, and Dr. Julie Vose as temporary voting members for the committee discussions.

Based on the agenda made available and on relevant data reported by participating members and consultants, it has been determined that all financial interests in firms regulated by the Center for Biologics Evaluation and Research that may be affected by the committee's discussions have been considered. The following participants have been granted waivers, in accordance with 18 U.S.C. 208, which permits them to participate fully in the committee discussions: Drs. Hugh Auchincloss, Virginia Broudy, Richard Champlin, Carole Miller, and Julie Vose. Dr. Michael O'Fallon has requested to be recused from the discussion of the report of the Xenotransplantation Subcommittee.

In the event that the discussions involve specific products or firms not on the agenda for which FDA's participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the public record.

Screenings were conducted to prevent any appearance, real or apparent, of conflict of interest in today's committee discussions. Copies of the waivers addressed in this announcement are available by written request under the Freedom of Information Act.

With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they wish to comment upon.

DR. SALOMON: Thank you, Gail.

Are there any other comments from the FDA staff we need to deal with?

(No response.)

DR. SALOMON: I'm going to, as Chairman, try and stay on time but, in the same way, allow everybody to participate in the discussion as much as possible.

Obviously, for recording interests, it's going to be important for us, as usual, to make an effort to speak directly into the microphones. I apologize if we have to remind anybody of that. I usually forget myself.

Then I'd like to open up the public hearing. We have one scheduled speaker which is Dr. Thomas Schaible, Senior Director of Immunology and Medical Affairs for Centocor. Welcome, Dr. Schaible.

DR. SCHAIBLE: Thank you. Good morning. We appreciate the opportunity to share our experience at Centocor regarding immune responses to therapeutic biologics.

This morning I'd like to touch upon a few of the key issues revolving around immune responses and, more specifically, share with you our experience with two of our products, Remicade and ReoPro, and then finish up my presentation with some conclusions based upon that experience.

Now, certainly one of the key issues with biologics is their potential antigenicity, and if antibodies develop against these agents, what is the clinical relevance both in terms of safety, whether there are potential allergic reactions or hypersensitivity that may result from these antibodies, but also in terms of efficacy, is there potential for blocking antibodies that may result in reductions in potency of these agents.

I think as a quick background, it's important to recognize that a number of biologic agents, both recombinant molecules, as well as monoclonal antibodies, do develop antibodies at varying incidences as well as magnitudes.

Now, in terms of our own experience, I'll focus on our two products: Remicade, which is infliximab, and ReoPro, which is abciximab. I think it's important to point out some important differences in these products both in terms of the molecules themselves, but also in terms of the diseases in which these agents have been developed.

First of all, with Remicade, Remicade is a whole chimeric IgG. It has a long serum half-life of approximately 10 days. It has been developed primarily in the treatment of chronic inflammatory disorders. Therefore, multiple dose regimens have been a key part of that development, and it has been used both with and without concurrent immunosuppressive agents.

With regard to ReoPro, abciximab, it is a chimeric Fab fragment. It has a short free serum half-life, less than 10 minutes. In part, that's due to the fact that it immediately binds to platelets after it's administered intravenously. It has been developed for treatment of acute coronary syndromes, and as such, it has been given primarily as a single dose, but it's important to recognize that because of recurrence of these types of syndromes, there's clearly a potential for readministration of this agent.

In terms of the development of Remicade in chronic inflammatory diseases, we have extensive clinical trial experience now both in Crohn's disease, which is an inflammatory bowel disease, as well as rheumatoid arthritis, and this experience includes both experience with single-dose regimens, as well as longer-term repeated dosing regimens.

In terms of experience with single-dose regimens, in Crohn's disease, we have observed a 13 percent incidence of human anti-chimeric antibodies, or HACA. Generally these are of low titer, less than 1 to 80. The incidence is lower in patients who receive concurrent immunosuppressants such as Immuran, such as 6MP. This incidence is about two-fold lower in patients receiving concurrent immunosuppressants.

In addition, we have observed some delayed hypersensitivity events, but specifically this has occurred in patients who have had a long interval, that is, 2 to 4 years, between exposures to the agent.

Now, in rheumatoid arthritis, we have a more substantial experience with long-term repeated dose regimens. In these studies, doses were given at 0, 2, and 6 weeks, and then every 4 or 8 weeks thereafter. We have studied doses of 1, 3, or 10 milligrams per kilogram, and we have studied these doses both with and without current methotrexate treatment which is the immunomodulator that is currently one of the standards of treatment in RA.

Now, in our phase II experience, we observed that both dose and concurrent methotrexate treatment were important in the incidence of HACA development. First of all, what we observed was that lower doses of Remicade were associated with higher incidences of HACA. In addition, if Remicade was given in combination with methotrexate, this also had the effect of reducing the incidence of HACA.

Now, in our phase III program, because of these findings, as well as a number of other reasons, we selected to study doses of 3 and 10 milligrams per kilogram given in combination with methotrexate.

One of the key issues here is to establish how well these agents are tolerated over time when they are given repeatedly. I think our experience in our phase III trial, which is called the ATTRACT trial, has been very helpful in getting a better understanding of this.
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